A novel protecting group methodology for syntheses using nitroxides

Article abstract of DOI:10.1039/c3cc46146g

The methoxyamine group represents an ideal protecting group for the nitroxide moiety. It can be easily and selectively introduced in high yield (typically >90%) to a range of functionalised nitroxides using FeSO ₄·7H₂O and H₂O₂ in DMSO. Its removal is readily achieved under mild conditions in high yield (70-90%) using mCPBA in a Cope-type elimination process.

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A Novel Protecting Group Methodology for Syntheses using Nitroxides
Benjamin A. Chalmersa, Jason C. Morrisa, Kathryn E. Fairfull-Smitha, Richard S. Graingerb and Steven
E. Bottlea*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5 DOI: 10.1039/b000000x
(Scheme 1).
The methoxyamine group represents an ideal protecting
group for the nitroxide moiety. It can be easily and selectively
introduced in high yield (typically >90%) to a range of
functionalised nitroxides using FeSO4.7H2O and H2O2 in
10 DMSO. Its removal is readily achieved under mild conditions
in high yield (70-90%) using mCPBA in a Cope-type
elimination process.
50
Scheme 1 Introduction and removal of the methoxyamine nitroxide
protecting group.
55 In previous nitroxide syntheses, protection of the nitroxide
moiety has been achieved using an acetate group which can be
subsequently removed with strong base.15b,16 However, this group
may be unsuitable for a number of nucleophilic reactions as it
contains a reactive ester moiety. Benzyloxyamines have also been
60 employed as protecting groups but can provide low yields upon
deprotection via hydrogenolysis in glacial acetic acid.12c The
secondary amine precursor is a common synthetic intermediate
for most hindered nitroxides, but these can be sensitive to
autooxidation and can introduce difficulties in syntheses
65 involving nucleophilic attack. Resolution on chromatography can
also prove challenging for these amines.
We envisaged the methoxyamine group to be the ideal
nitroxide protecting group as it imparts minimal structural change
on the physical properties of the parent nitroxide, is stable under
70 acidic and basic conditions and is inert to a number of typical
functional group transformations. Furthermore, nuclear magnetic
resonance analysis is facilitated through the introduction of a
sharp 3H signal. (Nitroxides are paramagnetic and typically give
significantly broadened NMR signals, so the reversible
75 transformation to a functionality with a clear 3H integral aids
structural elucidation).
To demonstrate the versatility of the methoxyamine group as a
suitable nitroxide protecting group, we examined its introduction
to, and removal from, a variety of functionalised nitroxides
80 (containing halides, amines, carbonyls, alkynes and conjugated
systems). The selection was largely based upon the isoindoline
class of nitroxides due to the presence of an inherent
chromophore which aided chromatographic analysis of the
reaction, however 4-benzyloxy-2,2,6,6-tetramethylpiperidin-1-
85 oxyl (8) was also selected to examine the applicability of this
method towards the piperidine class of nitroxides.
Nitroxides are versatile and stable free radical species that have
been extensively studied for more than 50 years. The broad
15 interest in nitroxides arises from their applications across a range
of scientific disciplines including materials science, molecular
biology, biophysics and medicine.1 Nitroxides have been widely
employed as initiators for the preparation of well-defined,
functional and complex polymers2 and nitroxide radical
20 precursors are commonly used as stabilisers in materials.3 The
nitroxide moiety also provides an excellent synthetic handle for
additional functionalization of polymers4 and surfaces.5 The use
of nitroxides as spin-labels has enabled investigation into the
molecular structure, dynamics and functional activity of various
25 biomolecules.1b,6 More recently, nitroxides have been exploited to
prepare organic magnets7 and as dynamic nuclear polarization
agents for the enhancement of NMR signals.8 The ability of
nitroxides to undergo redox chemistry has further widened the
scope of their applications. Their use as antioxidants in conditions
30 involving oxidative stress is well documented1b,9 and they display
significant potential as redox mediators for dye-sensitised solar
cells10 and as cathodic materials in organic batteries.11
To cater for the diverse fields in which nitroxides are currently
utilized, a number of synthetic strategies have been devised in
35 order to develop tailored nitroxides for specific applications.
Although the nitroxide moiety displays remarkable robustness in
several different reaction types (e. g. Pd-catalysed cross-
couplings,12 the copper-catalysed azide-alkyne 1,3-dipolar
cycloaddition reaction13 and ring closing metathesis14), it is
40 unstable in the presence of strong acid and base, radical driven
reactions and strong oxidants and reductants.15 To overcome the
susceptibility of the nitroxide functionality to these conditions
and extend nitroxide syntheses to access previously unobtainable
structural variations, we sought an appropriate protecting group
45 strategy. We herein report that the conversion to a methoxyamine
group and cleavage under mild conditions in good yield
represents a convenient and simple protecting group strategy for a
range of nitroxide classes bearing different functionalities.
The synthesis of methoxyamine derivatives of nitroxides has
been previously achieved via two main methods: reaction with
methyl radicals (generated either though Fenton chemistry in
90 DMSO17
or
the
CuCl-catalysed
decomposition
of
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Table 1 Formation of methoxyamines from nitroxides using H2O2 and FeSO4.7H2O in dimethylsulfoxide and deprotection with mCPBA.
Entry
Methoxyamine
Formation
Isolated
yield
Nitroxide
Regeneration
mCPBA
(equiv.)
Time
(hr)
Isolated
yield
1
2
2.1
4.2
0.5
0.1
85%
80%
74%a
3
4
2.1
4.2
0.5
0.1
88%
86%
96%
88%
5
6
3.0
2.5
2.0
1.0
88%
84%
(from 3b)
68%a
7
8
2.5
3.0
1.0
8.0
75%
37%
85-95%
(80% over
2 stepsc)
9
95%
87%
2.1
0.5
67%
10
3.0
1.0
85%
a
Compounds 1 and 7 are formed in high yield from the nitroxides 2 and 8 , however they are volatile and provide lower isolated yields due to loss of product upon workup in vacuo. Successful protection
and deprotection for the even more volatile parent TEMPOL was also achieved, details of which are provided in the Supplementary Information.
b
See Supplementary Information for synthetic procedure.
Compound 9 can be formed from the nitroxide in good yield or synthesised from the arylhalide in two steps as previously described.12c
c
5
aldehyde/ketone peroxide intermediates18) or reduction of the
nitroxide to the corresponding hydroxylamine and subsequent
Information.
In the absence of sensitive functionalities, such as the simple
reaction with an alkyl halide.19 Our preference has been to use 35 alkyl substituted aryl system 1, the mCPBA promoted
Fenton chemistry as the reaction is fast, tolerates a wide range of
deprotection occurs more readily when larger amounts of
10 functional groups and does not require an inert atmosphere.
Accordingly, a range of methoxyamines 1, 3, 5, 7, 9, 11 and 13
were prepared in high yield (typically over 90%) by reacting the
corresponding nitroxides with FeSO4.7H2O and H2O2 in DMSO.
N-Alkoxyamines have been previously cleaved using
15 diammonium cerium(IV) nitrate at elevated temperatures (70 °C),
however over-oxidation results in the formation of the
oxoammonium species which may readily decompose.20 We now
report that removal of the methyl protecting group can be readily
facilitated by oxidation with 3-chloroperoxybenzoic acid
20 (mCPBA) in DCM in a Cope-type elimination reaction that
precludes other functional group modification and provides high
yields of the desired nitroxide (Table 1).
mCPBA are used (Table 1, entries 1 and 2).
40
45
Typically, mCPBA has been used synthetically as an oxidant
in the oxidation of ketones, amines and sulfides, most notably in
25 the Baeyer-Villiger and Rubottom oxidations, as well as being
utilised in the Prilezhaev epoxidation of alkenes.21 Furthermore,
mCPBA has been demonstrated to be a mild oxidant capable of
producing N-oxides via electrophilic attack at nitrogen.22
Subsequent oxygen transfer yields a substrate that is primed for
30 Cope elimination.23 The mechanism for the application in this
context is proposed in Scheme 2. GCMS evidence for the
formation of formaldehyde is provided in the Supplementary
Scheme 2 Proposed deprotection mechanism via N-oxidation and
subsequent Cope-type elimination.
Similarly, the presence of aryl halides has little impact on the
50 nitroxide yield when using excess mCPBA (Table 1, entries 3 and
4). Notably, deprotection of the methoxyamine 5 occurs in high
yield (88%) even in the presence of aldehydes (Table 1, entry 5).
The TEMPO-based methoxyamine 7 also underwent efficient
deprotection in high yield (Table 1, entry 6), and this result
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60 2 (a) J. Nicolas, Y. Guillaneuf, C. Lefay, D. Bertin, D. Gigmes and B.
Charleux, Prog. Polym. Sci., 2013, 38, 63-235; (b) C. J. Hawker, A.
W. Bosman and E. Harth, Chem. Rev., 2001, 101, 3661-3688.
further highlights that benzyl ethers remain unaffected under
these conditions. In the case of anthracene methoxyamines such
as 9, deprotection was observed to produce the nitroxide 10 in
good yield (75%), however small amounts of fluorescent side-
5 products were also detected (Table 1, entry 7 and 8). These 65
products are expected to arise from partial oxidation of the
anthracene core to give substituted anthraquinones, perhaps via
the corresponding endoperoxides.24 Notably, the formation of by-
products could be minimised using shorter reaction times and
10 decreased equivalents of mCPBA. In the presence of anthracenes
with alkyne side-chains, such as in 11, the deprotection gave the
desired nitroxide 12 in reasonable yield (67%) along with similar
3
(a) G. Gryn'ova, K. U. Ingold and M. L. Coote, J. Am. Chem. Soc.,
2012, 134, 12979-12988; (b) Gugumus, F. in Handbook of Polymer
Degradation, 2nd ed.; Halim Hamid, S., Ed.; Marcel Dekker: New
York, 2000; p 1; (c) K. E. Fairfull-Smith, J. P. Blinco, D. J. Keddie,
G. A. George and S. E. Bottle, Macromolecules, 2008, 41, 1577-
1580.
(a) J. P. Blinco, K. E. Fairfull-Smith, A. S. Micallef and S. E. Bottle,
70 4 Polym. Chem. 2010, 1, 1009-1012; (b) J. Kullis ,C. A. Bell, A. S.
Micallef, Z. Jia and M. Montiero, Macromolecules, 2009, 42, 8218-
8227.
5
(a) J. P. Blinco, B. A. Chalmers, A. Chou, K. E. Fairfull-Smith and S.
E. Bottle, Chem. Sci., 2013, 4, 3411-3415; (b) H. Wagner, M. K.
Brinks, M. Hirtz, A. Schäfer, L. Chi, and A. Studer, Chem. Eur. J.,
2011, 17, 9107 – 9112.
fluorescent by-products as were seen with 9. These by-products
75
may also include small amounts of peracid oxidation of the
15 alkyne (Table 1, entry 9).25 Again, these side reactions could be
minimised by immediate quenching of the reaction upon
6
S. A. Shelke and S. T. Sigurdsson in Spin-labels and Intrinsic
Paramagnetic Centers in the Biosciences: Structural Information
From Distance Measurements, Structure and Bonding Book Series;
C. Timmel, Ed; Springerlink, 2011, 1-42.
consumption of the starting material (followed via TLC). The
80
nitro group was shown to be quite stable under the deprotection
conditions with a high yield (85%) of nitroxide 14 arising from
20 the treatment of methoxyamine 13 (Table 1, entry 10). However,
7
8
I. Ratera and J. Veciana, Chem. Soc. Rev., 2012, 41, 303–349.
A. Zagdoun, G. Casano, O. Ouari, M. Schwarzwälder, A. J Rossini,
F. Aussenac, M. Yulikov, G. Jeschke, C. Coperet, A. Lesage, P.
Tordo and L. Emsley, J. Am. Chem. Soc., 2013, doi:
10.1021/ja405813t.
(a) D. I. Pattison, M. Lam, S. S. Shinde, R. F. Anderson and M. J.
Davies, Free Rad. Biol. Med., 2012, 53, 1664-1674; (b) J. R. Walker,
K. E. Fairfull-Smith, K. Anzai, S. Lau, P. J. White, P. J. Scammells
and S. E. Bottle, Med. Chem. Commun., 2011, 2, 436-441; (c) K.
Hosokawa, P. Chen, M. F. Lavin and S. E. Bottle, Free Rad. Biol.
Med., 2004, 37, 946-952.
attempted
deprotection
of
5-amino-2-methoxy-1,1,3,3-
85
90
95
tetramethylisoindoline by mCPBA gave multiple products after
only a few minutes, as indicated by TLC, consistent with
competitive oxidation of the primary aryl amine.
9
25 We have shown the methoxyamine group to be a highly
efficient, chemically robust protecting group for nitroxide
syntheses. The introduction of the methyl group was achieved for
a variety of nitroxides under mild conditions and in high yield
using methyl radicals generated from DMSO, ferrous ions and
30 hydrogen peroxide. Removal of the methyl protecting group was
readily achieved using mCPBA in DCM in the presence of a
variety of functional groups. The facile nature of the Cope-type
elimination allows for the methyl ether to be readily cleaved
10 G. Gryn'ova, J. M. Barakat, J. P. Blinco, S. E. Bottle and M. L. Coote
Chem. - Eur. J., 2012, 18, 7582-7593; (b) Z. Zhang, P. Chen, T. N.
Murakami, S. M. Zakeeruddin and M. Graetzel, Adv. Funct. Mater.,
2008, 18, 341-346.
11 T. Ibe, R. B. Frings, A. Lachowicz, S. Kyo and H. Nishide, Chem.
Commun., 2010, 46, 3475-3477; (b) T. Janoschka, M. D. Hager and
U. S. Schubert, Adv. Mater., 2012, 24, 6397-6409.
(a) D. J. Keddie, T. E. Johnson, D. P. Arnold and S. E. Bottle, Org.
before any significant side reactions occur. If side reactions are100 12 Biomol. Chem., 2005, 3, 2593-2598; (b) D. J. Keddie, K. E. Fairfull-
Smith and S. E. Bottle, Org. Biomol. Chem., 2008, 6, 3135-3143; (c)
35 possible through over oxidation, then careful monitoring of the
K. E. Fairfull-Smith and S. E. Bottle, Eur. J. Org. Chem., 2008, 32,
5391-5400.
reaction and the use of limited amounts of mCPBA can still
provide the nitroxide in good yield. In this way, deprotection can
13 J. C. Morris, J. C. McMurtrie, S. E Bottle and K. E. Fairfull-Smith, J.
be induced in good to high yields (67-88%). This new nitroxide
protecting group strategy should now enable a large range of
40 synthetic transformations that were not previously possible in the
presence of the nitroxide radical and thereby substantially
broaden the scope of possible nitroxide applications.
105
Org. Chem., 2011, 76, 4964-4972.
14 T. Kalai, B. Bognar, D. Zsolnai, Z. Berente and K. Hideg, Synthesis,
2012, 24, 3655-3660.
15 (a) K. E. Fairfull-Smith, E. A. Debele, J. P. Allen, M. C. Pfrunder
and J. C. McMurtrie, Eur. J. Org. Chem., 2013, 22, 4829-4835; (b) T.
Kálai, E. Borza, C. Antus, B. Radnai, G. Gulyás-Fekete, A. Fehér, B.
Sümegi and K. Hideg, Bioorg. Med. Chem., 2011, 19, 7311-7317.
16 K. E. Fairfull-Smith, F. Brackmann and S. E. Bottle, Eur. J. Org.
Chem., 2009, 12, 1902-1915.
110
Notes and references
aARC Centre of Excellence for Free Radical Chemistry and
45 Biotechnology, Faculty of Science and Engineering, Queensland
University of Technology, 2 George St, Brisbane, QLD 4001, Australia
Fax: +61-7-31381804; Tel: +61-7-31381356; E-mail: s.bottle@qut.edu.
b School of Chemistry, University of Birmingham, Edgbaston,
(a) J. P. Galbo, United States Patent, 1993, US5374729 A; (b) H.-Y.
115 17 Ahn, K. E. Fairfull-Smith, B. J. Morrow, V. Lussini, B. Kim, M. V.
Bondar, S. E. Bottle and K. D. Belfield, J. Am. Chem. Soc., 2012,
134, 4721-4730.
18 K.-U. Schoening, W. Fischer, S. Hauck, A. Dichtl and M. Kuepfert,
J. Org. Chem., 2009, 74, 1567-1573.
50 B†iErmleicntgrohnaimc B15 2TT, UK
Supplementary Information (ESI) available: [Full
experimental procedures; 1H and 13C NMR spectra for compounds 1, 3, 5,
7 and 13; HPLC chromatograms for compounds 1, 2, 5-8, 13 and 14]. See
DOI: 10.1039/b000000x/
120 19 D. Gigmes, A. Gaudel-Siri, S. R. A. Marque, D. Bertin, P. Tordo, P.
Astolfi, L. Greci and C. Rizzoli, Helv. Chim. Acta, 2006, 89, 2312-
2326.
20 G. O'Brya and R. Braslau, Macromolecules, 2006, 39, 9010-9017.
21 S. D. Burke and R. L. Danheiser, Handbook of Reagents for Organic
Synthesis: Oxidizing and Reducing Agents; Wiley: Chichester, 1999.
22 (a) L. R. Subbaraman, J. Subbaraman and E. J. Behrman,
Biochemistry, 1969, 8, 3059-3066; (b) J. C. Craig and K. K.
Purushothaman, J. Org. Chem., 1970, 35, 1721-1722.
(a) L. Teben and A. Studer, Angew. Chem., 2011, 50, 5034-5068; (b)
55 1 G. Likhtenshtein, J. Yamauchi, S. Nakatsuji, A. I. Smirnov and R.
Tamura, Nitroxides: Applications in Chemistry, Biomedicine, and125
Materials Science.; Wiley-VCH: Weinheim, 2008; (c) J. P .Blinco, B.
J. Morrow, K. E. Fairfull-Smith and S. E. Bottle, Aust. J. Chem.,
2011, 64, 373-389.
130 23 Lett. 1986, 27, 1119-1122.
M. F. Semmelhack, C. R. Schmid and D. A. Cartes, Tetrahedron

View Article Online
ChemComm
DOI: 10.1039/C3CC46P14a6gGe 4 of 4
24 N. Safari, S. S. Naghavi and H. R. Khavasi, Applied Catalysis A:
General, 2005, 285, 59-64.
25 J. Ciabattoni, R. A. Campbell, C. A. Renner and P. W. Concannon, J.
Am. Chem. Soc., 1970, 92, 3826–3828.
5